tbuckley/cabot-search huggingface dataset:
Endocrine therapy resistance (ETR) in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+, HER2– mBC): Prevalence, biomarker characteristics, and outcomes.
Authors: Rinath Jeselsohn, Lu Chen, Nayan Chaudhary, Jorge Martinalbo, Peter A. Fasching, Marc Hafner, Patricia Luhn, Alberto J. Montero, Pablo Diego Pérez-Moreno, Seth Andrew Wander, Kevin Kalinsky
Journal: Journal of Clinical Oncology (2023)

1062 Background: ETR to prior adjuvant ET poses challenges to first-line treatment (1L tx) of HR+, HER2– mBC. Understanding patient (pt)/disease heterogeneity is crucial for developing new txs that target specific ETR mechanisms to improve pt outcomes. We investigate ETR, including prevalence, genomic profiles, and survival outcomes in pts with HR+, HER2– mBC treated in the 1L setting. Methods: This retrospective two-cohort study of pts initiating 1L systemic tx for mBC (diagnosed after Jan 1, 2015) used data from the Flatiron Health (FH) electronic health record-derived de-identified database (FH cohort), and FH-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB cohort; solid biopsy FMI test required). The de-identified data originated from ~280 US cancer clinics (~800 sites of care). Pts with ETR to prior adjuvant ET were defined per ESMO guidelines (table footnote); primary ETR (1ETR) was divided into pts relapsing within 1 year (yr) or 1–2 yrs of adjuvant ET. Genomic profiles were assessed in the CGDB cohort. In both cohorts, real-world (rw) progression-free survival (PFS) and overall survival (OS) were estimated in pts who received 1L tx with fulvestrant (F) + CDK4/6 inhibitor (CDK4/6i). Results: In the FH cohort (N = 4052), 16.1% of pts had 1ETR (ET &lt;1 yr: 7.9%) and 33.9% had secondary ETR (2ETR). In the CGDB cohort (N = 696), ESR1 mutations (ESR1m) were present in 10.8% of 158 pts with 1ETR (ET &lt;1 yr: 4.2%; 1–2 yrs: 16.1%) and 19.9% of 317 pts with 2ETR. In pts who received 1L F + CDK4/6i, shorter median (m) rwPFS (statistically significant) and OS (not significant) were seen in pts with 1ETR vs. 2ETR, but outcomes were not affected by the presence of ESR1m in pts with 2ETR. Conclusions: Overall, half of pts with 1L HR+, HER2– mBC have ETR to prior adjuvant ET. Pts with ETR have tumors with heterogeneous genomic profiles and varied survival outcomes. ESR1m are infrequent in pts with 1ETR and &lt;1 yr of adjuvant ET but are more common in 2ETR. In pts treated with 1L F + CDK4/6i, PFS and OS were worse with 1ETR than 2ETR. This study highlights the importance of further understanding the heterogeneity in molecular profiles and outcomes within ETR. [Table: see text]
Deep learning to estimate RECIST in patients with cancer treated in real-world settings.
Authors: Irbaz Bin Riaz, Noman Ashraf, Gordon J Harris, Toni K. Choueiri, Kenneth L. Kehl
Journal: Journal of Clinical Oncology (2023)

1564 Background: Creating large oncology clinical-genomic datasets is laborious and time-consuming. Deep learning approaches that extract RECIST outcomes at scale from observational electronic health records (EHR) data could tremendously facilitate precision oncology research. Methods: This retrospective study included patients with solid tumors treated on therapeutic clinical trials from 2004-2022 at Dana-Farber Cancer Institute with radiology reports in EHR and RECIST labels available from the tumor imaging metrics core. Each RECIST label was generated using corresponding radiology reports at a given time point. Patients were sampled into training, validation, and held-out test sets. A deep learning model (RECIST model) was trained to predict two outcomes: overall response and progressive disease at each time point, using reports from that time point and prior time points for each patient. This trained RECIST deep learning model was deployed on real-world radiology reports, and results were compared with true labels abstracted by trained human curators using the PRISSMM framework. Results: This study included 5153 patients with a total of 99,318 radiological reports who had RECIST annotations (median age at protocol enrollment [IQR] 60 years [52-57]; females 61% [3133]; and white 90% [4653]). The most common cancer types included breast (n=1006; 20%) lung (n=573; 11%), and ovarian cancer (n=539; 10%). The training subset included 4121 (79.9%) patients, the validation subset 518 (10.1%), and the held-out test set 514 (9.9%) patients. In the test set, the results showed an AUC of 0.86, and 0.87 with the best F1 scores of 0.72 and 0.63 for predicting overall response, and progressive disease, respectively. The real-world data set included 4482 patients. RECIST model evaluation on real-world radiology reports showed good performance for ascertaining PRISSMM annotations of progression from those reports (AUC 0.83, best F1 0.68), but poor performance for ascertaining PRISSMM annotations of response (AUC 0.63, best F1 0.28). Evaluation metrics are outlined in the Table. Conclusions: This study demonstrated the feasibility of using deep learning approaches to predict RECIST outcomes from radiology reports for patients with solid cancer tumors. The results show that the deep learning model accurately predicted RECIST labels on a held-out test set and real-world radiology reports for the outcome of progressive disease. These findings could accelerate precision oncology research providing a scalable way of ascertaining cancer outcomes from observational EHR data.[Table: see text]
The mutational landscape of Chinese breast cancer by liquid biopsy.
Authors: Jing Fan, Yan Yin, Bo Hu, Bo Peng
Journal: Journal of Clinical Oncology (2023)

e13117 Background: Breast cancer is the most common malignancy worldwide. The novel technique of liquid biopsy provides further prospect of breast cancer management. However, the clinical application of liquid biopsy for breast cancer remains clearly defined. Methods: Blood samples of 145 Chinese patients diagnosed as breast cancer were collected. cfDNA were analyzed by next-generation sequencing technique using Haplox HapOnco panel. The mutations of cfDNA were analyzed and compared with genomic mutations detected within tumor tissues of breast cancer patients. Results: In total, 327 genetic mutations were detected in 145 patients using cfDNA. The top 5 high frequent alterations were TP53(50.3%), PIK3CA (42.8%), SYNE1 (16.6%), ESR1 (10.3%), CSMD3 (9.0%). Within TP53 mutations, 13.7% were frame shift insertions or deletions, 5.5% were in-frame insertions or deletions, 9.6% were splice site mutations. Within PIK3CA mutations, 1.6% were in-frame insertions or deletions, 1.6% were copy number variations. The average number of mutations for each patient was 7.2 (5.5 to 9.0, 95% CI). The mutated genes in cfDNA were compared with those in tumor tissues in publications. 208 mutated genes in tumor tissues were also detected in cfDNA. There was no significant difference in mutation rate for 83.6% genes in blood and tumor tissues. Conclusions: Most mutated genes in tumor tissues of breast cancer patients could be detected in cfDNA. The mutation rate for most genes had no significant difference in blood and tumor tissues, which indicated that liquid biopsy using cfDNA is a promising technique to improve breast cancer management.
Exploring the effects of inhibiting miR-10b on breast cancer stemness and metastasis.
Authors: Nasreen Al-Qadi, Alan Halim, Hussein Mackie, Lorenzo Sempere, Anna Moore
Journal: Journal of Clinical Oncology (2023)

e13084 Background: There are currently limited effective therapeutic options for metastatic breast cancer, and none target the metastatic process. MiR-10b is a major driver of breast cancer cell invasion and migration. Our lab has demonstrated its importance in metastatic cell viability, positioning miR-10b as a target for metastatic breast cancer. Our previous studies demonstrated that delivery of a novel therapeutic consisting of antisense anti-miR-10b oligomers conjugated to magnetic nanoparticles (termed MN-anti-miR10b) prevented metastases in vivo. These studies led us to hypothesize that MN-anti-miR10b affects the viability of a stem cell-like population of cells within primary tumors that otherwise would have formed metastases. Here, we investigate the relationship between miR-10b and breast cancer cell stemness and the effects of miR-10b inhibition by MN-anti-miR10b on breast cancer cell stemness. Methods: MDA-MB-231 breast cancer cells were sorted based on surface markers into stem-like (CD44+/CD24-) and non-stem-like (CD44-/CD24-) populations, and their miR-10b expression levels were quantitated. Then, unsorted MDA-MB-231 cells were treated with MN-anti-miR10b to determine the effects of miR-10b inhibition on the expression of EPCAM, a marker for cancer cell stemness. Lastly, MCF-7 breast cancer cells were cultured in mammosphere medium (which selects for stem-like cells and induces spheroid formation) and treated with MN-anti-miR10b to establish the phenotypic effect of miR-10b inhibition on cancer cell stemness. Results: We found that stem-like MDA-MB-231 cells displayed &gt;2-fold miR-10b expression compared to non-stem-like cells. Accordingly, alongside a 70% reduction in miR-10b expression, treatment of MDA-MB-231 cells with MN-anti-miR10b reduced EPCAM expression by 65%. Treatment of MCF-7 spheroids with MN-anti-miR10b resulted in significantly greater cell dissociation from the spheroid compared to controls. Conclusions: These results support the hypothesis that inhibition of miR-10b with MN-anti-miR10b inhibits breast cancer cell stemness. This provides an explanation for the therapeutic efficacy of MN-anti-miR10b observed in mouse breast cancer metastasis models. Future studies will further investigate this relationship and shed light on how miR-10b can be optimally targeted to treat metastatic breast cancer in humans.
Outcomes according to treatment received for small node-negative HER2+ breast tumors in the Surveillance, Epidemiology, and End Results (SEER) database, 2010-2019.
Authors: Adrienne Gropper Waks, Paolo Tarantino, Rachel A. Freedman, Nancy U. Lin, Nabihah Tayob, Carlos Teodoro Vallejo, Julieta Leone, Sara M. Tolaney, Jose Pablo Leone
Journal: Journal of Clinical Oncology (2023)

517 Background: The magnitude of systemic therapy (tx) benefit for small, node-negative HER2+ breast tumors is unknown, with uncertainty about how benefit varies across stage I tumor sizes. We analyzed treatment patterns and outcomes for patients (pts) with stage IA (pT1N0) HER2+ breast cancer in the national SEER database. Methods: Pts with one lifetime diagnosis of pT1N0 HER2+ breast cancer between 2010-2019 were included. Receipt of chemotherapy (chemo) was categorized as yes vs no/unknown; receipt of endocrine tx is not available in SEER. All systemic tx was administered in the adjuvant setting. The primary outcome variable was breast cancer-specific survival (BCSS; recurrence events are not available in SEER), which was compared between treatment groups using a multivariate Cox model adjusted for age at diagnosis (dx), race, tumor grade/histology/size, hormone receptor (HR) status, radiation, marital status, income, rurality. Chemo use predictors were evaluated by multivariable logistic regression. Results: We identified 12,861 pts with pT1N0 HER2+ breast cancer; 9,513 (74%) HR-positive and 3,348 (26%) HR-. Median age at dx was 59 yrs. Median follow-up was 46 months. In the overall cohort, BCSS at 3, 5, and 7 yrs was: 99.3% (with chemo) vs 99.1% (without chemo); 98.6% (with chemo) vs 97.4% (without chemo); and 97.5% (with chemo) vs 96.4% (without chemo), respectively. Adjusted hazard ratio (HzR) for BCSS events in the chemo vs no chemo group of the overall cohort was 0.63 (p=0.004;). BCSS events by tumor size and HR status are shown; p values are not shown where event rates were too low to run an adjusted model. Chemo use increased significantly between 2010-2019 within each tumor size category (all p for trend &lt; 0.04), except for T1a HR+/HER2+ and T1mi HR-/HER2+. Pts were less likely to receive chemo if they were older, Hispanic (vs non-Hispanic White), separated/divorced/widowed (vs single), or had lower median household income (vs &gt;$75K). Pts were more likely to receive chemo if they had larger tumor size, HR- tumor, higher tumor grade, were married (vs single), or had later yr of dx. Conclusions: Receipt of chemo was associated with higher BCSS in the overall stage IA cohort and among pts with HR+/HER2+ stage IA tumors. Tumors ≤ 1cm had excellent outcomes with or without chemo. Sociodemographic factors including income, race, and marital status impacted chemo receipt. [Table: see text]
PLEASURABLE: Results and biomarkers analysis from the phase II study of dalpiciclib combined with pyrotinib and endocrine therapy (ET) in women with dual-receptor positive (ER+/HER2+) metastatic breast cancer (MBC).
Authors: Jian Zhang, Yanchun Meng, Biyun Wang, Xinhong Wu, Hongmei Zheng, Li Cai, Wenyan Chen, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Ni Sujie, Zhengyan Yu, XueSong Chen, Qiang Peng, Xin Hu, Wenqing Yao, Xichun Hu
Journal: Journal of Clinical Oncology (2023)

1046 Background: In the front-line setting, our previous work demonstrated an impressive median progression-free survival (PFS) of 11.3 months with 66.7% response rate, and concluded a recommended phase 2 dose of pyrotinib 320mg/d, dalpiciclib (SHR6390, a novel CDK4/6i) 125mg/d, and letrozole 2.5mg/d for HR+/HER2+ MBC patients (pts) (Xichun Hu, FRONT ONCOL 2022). Results and biomarkers analysis from phase II dose expansion study are presented. Methods: ER+/HER2+ MBC Pts eligible for first- or second-line treatment were enrolled to receive dalpiciclib combined with pyrotinib and ET (letrozole or fulvestrant determined by physician’s choice). The primary endpoint was objective response rate (ORR). For biomarkers analysis, 68 Ga-HER2 affibody, pre-treatment tissue-derived DNA and circulating tumor DNA (ctDNA) were assessed by PET/CT, and next-generation sequencing (NGS), respectively. Results: As of January 19, 2023, 48 pts were enrolled. 17 pts (35.4%) were treatment naïve, and 31 pts (64.6%) had received prior trastuzumab. The ORR was 68.1% (32/47) and disease control rate was 100% (47/47). In trastuzumab-naïve and trastuzumab-pretreated patients, ORR was 81.3% (13/16) and 61.3% (19/31), respectively. PFS and OS data were not mature by cut-off date. No new safety signals were observed. The most frequent treatment-related adverse events were neutropenia (95.8%; G3:60.4%, G4:6.3%), leukopenia (91.7%; G3:45.8%), diarrhea (87.5%; G3:2.1%), anemia (79.2%; G3:4.2%), oral mucositis (68.8%, G3:2.1%) and platelet count decreased (41.7%; G3:2.1%, G4:2.1%). The heterogeneity of 68 Ga-HER2 affibody uptake was observed among patients, both at baseline (N=16，median SUV max 7.5, range, 2.3-34.9) and after 2 cycles of therapy (N=12，median SUV max 4.0, range, 0-14.9). All patients with a decline in 68 Ga-HER2 affibody uptake (N=8) achieved partial response, while the uptake in non-responders was elevated (N=2). NGS was conducted to detect somatic and germline mutations in baseline tissue (n=10) and ctDNA (n=10) samples. Two patients with BRCA mutation (one had somatic BRCA1/ 2 mutation and another with germline BRCA2 mutation) had no tumor response. Conclusions: The chemotherapy-sparing regimens showed significant anti-tumor activity for ER+/HER2+ MBC pts in the front-line setting. The 68 Ga-HER2 affibody PET/CT may be a potential predictive biomarker of therapy response. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT03772353 .
Efficacy of antibody-drug conjugates in breast cancer: A systematic review and meta-analysis of randomized clinical trials.
Authors: Muhammad Ashar Ali, Wajeeha Aiman, Fatima Afzal, Hafsa Zahoor, Syeda Hafsa Kazmi, Aqsa Anwar, Ayfa Riaz Bajwa, Michael Maroules, Gunwant K. Guron, Hamid Salim Shaaban
Journal: Journal of Clinical Oncology (2023)

e13113 Background: Breast cancer (BC) is the 2 nd most common cause of cancer related deaths in women. Antibody-drug conjugates are monoclonal antibodies conjugated to the cytotoxic payload and are directed towards cell surface proteins specific to tumor cells. This systematic review and meta-analysis aims to assess the efficacy of ADCs in breast cancer and comparison of different ADCs. Methods: A literature search was performed on PubMed, Embase, WOS, and clinicaltrials.gov with key words “breast neoplasms,” and “immunoconjugates” from the inception of data till 6/6/2022. Cochrane and PRISMA guidelines were followed to establish guidelines registered on Prospero (CRD42022329529). Out of 4,570 articles, seven randomized clinical trials (RCTs, N=5,302) were included. R programming language software with “meta” package was used for this meta-analysis. Results: In 7 RCTs (N=5,302), 4,834 patients had HER-2 positive disease while 468 patients were triple negative BC (TNBC). 1,486 patients had residual invasive disease while 3,816 patients had metastatic breast cancer (mBC). 3,389 patients were treated with ADC (235 with sacituzumab govitecan (saci-gov), 2,339 with trastuzumab emtansine (T-DM1) and 261 trastuzumab deruxtecan (T-der)), 2,105 patients were treated with chemotherapy regimens. In 4 RCTs on HER-2 patients (N=2,825), pooled HR of PFS and OS were 0.72 (95% CI=0.61-0.84, I 2 =71%) and 0.73 (95% CI=0.64-0.84, I 2 =20%), respectively, in favor of ADC. Risk of ORR was 1.48 (95% CI=0.84-2.60, I 2 =91%) in favor of ADC. In RCT on TNBC (N=468), HR of PFS and OS were 0.55 (95% CI=0.51-0.61) and 0.59 (95% CI=0.54-0.66), respectively, in favor of saci-gov (ADC). In RCT on HER-2 positive residual invasive breast cancer, HR of recurrence/death was 0.61 (95% CI=0.54-0.69) in favor of T-DM1. In an RCT by Cortes et al. (N=524) comparing two ADCs in HER-2 mBC, the HR of PFS and OS were 0.28 (95% CI= 0.22-0.37) and 0.55 (95% CI=0.36-0.86), respectively, in favor of T-der as compared to T-DM1. The RR of ORR and CR were 2.33 and 1.28, respectively, in favor of T-der. Conclusions: ADCs are significantly more effective than chemotherapy in patients with HER-2 positive mBC, HER-2 positive residually invasive BC, and metastatic TNBC in terms of improving survival and response rates. Among ADCs, T-der was significantly more effective than T-DM1 in patients with HER-2 positive mBC. More double blinded multicenter RCTs are needed to confirm these results.
Prevalence of low HER2 expression in breast cancer patients: An Indian experience.
Authors: Ajay Gogia, Nithin S G, Sandeep Mathur, S.V.S. Deo, Shuvadeep Ganguly, Atul Batra, Dayanand Sharma, Chandra Prakash Prasad
Journal: Journal of Clinical Oncology (2023)

e12543 Background: With the recent advent of trastuzumab deruxtecan and encouraging results of the DESTINY-Breast-04 trial, low HER2 expression has emerged as a clinically significant therapeutic biomarker. The prevalence of low HER2 expression is unexplored in Indian population. Methods: This is a single center ambispective observational study conducted over a period of 4 years (1st January 2019 to 31st January 2023) at Dr. B.R.A, I.R.C.H, All India Institute of Medical Sciences (AIIMS), New Delhi, India. Consecutive female breast cancer patients registered during the study period with available clinical-pathological details were eligible for study inclusion. The primary objective of the study was to assess the prevalence of HER2 low breast cancer. HER2 low was defined as having HER expression by immunohistochemistry (IHC) of 1+ or 2+ with no amplification of the HER2gene detected with a fluorescent in situ hybridization (FISH) assay. Patients were divided into three categories: HER-2 high (IHC3+, IHC2+/FISH+), HER-2 low (IHC 1+, IHC2+/FISH-), and HER2-0 (HER2 negative, IHC:0). Staging description of the cases were done as per anatomic TNM classification according to AJCC 7 th edition. Results: A total of 2200 female breast cancer were registered during the study period, of which 1932 patients had available clinical-pathological details. Among 1932 patients, 600 patients (31%) had high HER2 expression and remaining 1332 patients had HER2 low/HER2-0 expression. Of the 1332 cases, the median age was 49 years (range 18–91 years). The stage distribution was stage I, 94 (7.06%); stage II, 409 (30.70%); stage III, 528 (39.64%); and stage IV, 301 (22.59%). Eight hundred patients (60.06%) were hormone positive, and 532 (39.94%) cases were hormone negative. The prevalence of HER2 low expression was 798 (59.9%). It was observed in 640 (80%) of hormone positive cases and 158 (29.69%) hormone-negative cases (p &lt; 0.001). Rest 534 cases were HER2 0 [160 cases (20%) were hormone positive, and 374 cases (70.31%) were hormone negative]. Conclusions: This is the first study from India to document the prevalence of low HER2 expression in female breast cancers. We observed the prevalence to be around 60 % in our population, which is more in hormone receptor-positive breast cancer. The estimated prevalence is higher than that observed in Western population, and it underscores the need to systematically categorize these patients for therapeutic decision making at presentation.
Disease-free survival (DFS) as a surrogate for overall survival (OS) in patients (pts) with HR+/HER2− early breast cancer (EBC): A correlation analysis.
Authors: Michael Untch, David Pérol, Erica L. Mayer, Javier Cortes, Arnd Nusch, David A. Cameron, Carlos Barrios, Thomas E. Delea, Tonatiuh Romero Salas, Manik Kalra, Rhea Gupta, Purnima Pathak, Peter A. Fasching
Journal: Journal of Clinical Oncology (2023)

535 Background: DFS has been widely adopted as a clinically meaningful primary endpoint in EBC trials in place of OS, which needs extensive follow-up to observe sufficient events and fails to assess survival benefit early. However, a rigorous validation of DFS as a surrogate endpoint for OS is required for each given setting. The objective of this analysis was to evaluate DFS as surrogate for OS in the adjuvant treatment of HR+/HER2− EBC. Methods: A systematic literature review (SLR) was conducted using biomedical literature databases (ie, Embase, PubMed, and Medline [from database inception to January 2023]) and key conferences to identify published studies in EBC. The eligibility criteria for the SLR were RCTs that included ≥80% of adult pts with HR+/HER2− EBC and assessing different treatment options (ie, cyclin-dependent kinase 4/6 inhibitors [CDK4/6i], endocrine therapies [ET], and chemotherapies [CT]). Studies were considered for correlation analysis if hazard ratios (HRs) were reported for both DFS and OS. The analysis excluded observational studies and trials with immature OS data. Spearman rank correlation (r s ) and weighted linear regression analyses (measured by coefficient of determination [R 2 ]) were performed to evaluate the correlation between HRs for OS and DFS. Considering heterogeneity, multiple scenario analyses were conducted. Surrogate threshold effect (STE) was also estimated; STE is defined as the maximum value of the HR for DFS that needs to be observed in a trial to ensure the possibility of concluding that a significant effect on OS occurred. Correlation was also assessed using pt-level data from the FACE trial (letrozole vs anastrozole in postmenopausal pts with HR+/HER2− EBC) to validate findings of the trial-level analysis. Results: A total of 14 RCTs (N = 31,668) were included (CDK4/6, 2; ET, 7; CT, 5). Trial-level analysis showed that r s between OS and DFS was 0.81 (95% CI, 0.56-0.94), which when weighted by variance was 0.81. Regression analysis showed that 84% of the variability in OS was explained by DFS (R 2 = 0.84). A meta-regression model estimated an STE of 0.82 for HR of DFS, which can be leveraged to validate the surrogacy based on the DFS estimated from a future trial. Analysis of pt-level data from the FACE trial demonstrated a correlation between DFS and OS (r s = 0.75). Additionally, correlation coefficients estimated by the Pearson method and iterative imputation were 0.83 and 0.89, respectively. Conclusions: Both trial-level and pt-level analyses demonstrate a positive correlation between DFS and OS. These results support the use of DFS as a reliable surrogate endpoint for OS in HR+/HER2− EBC trials to give an early access to innovative therapies.